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Mutations in PSEN1 and PSEN2 genes account for the majority of cases of early-onset familial Alzheimer disease. Since the first prediction of a genetic link between PSEN1 and PSEN2 with Alzheimer's disease, many research groups from both academia and pharmaceutical industry have sought to unravel how pathogenic mutations in PSEN cause presenile dementia. PSEN genes encode polytopic membrane proteins termed presenilins (PS1 and PS2), which function as the catalytic subunit of γ-secretase, an intramembrane protease that has a wide spectrum of type I membrane protein substrates. Sequential cleavage of amyloid precursor protein by BACE and γ-secretase releases highly fibrillogenic β-amyloid peptides, which accumulate in the brains of aged individuals and patients with Alzheimer's disease. Familial Alzheimer's disease-associated presenilin variants are thought to exert their pathogenic function by selectively elevating the levels of highly amyloidogenic Aβ42 peptides. In addition to Alzheimer's disease, several recent studies have linked PSEN1 to familiar frontotemporal dementia. Here, we review the biology of PS1, its role in γ-secretase activity, and discuss recent developments in the cell biology of PS1 with respect to Alzheimer's disease pathogenesis. 相似文献
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The polypeptide hormone Islet Amyloid Polypeptide (IAPP, amylin) is responsible for islet amyloid formation in type-2 diabetes and in islet cell transplants, where it may contribute to graft failure. Human IAPP is extremely amyloidogenic and fewer inhibitors of IAPP amyloid formation have been reported than for the Alzheimer's Aβ peptide or for α-synuclein. The ability of a set of hydroxyflavones to inhibit IAPP amyloid formation was tested. Fluorescence detected thioflavin-T-binding assays are the most popular methods for measuring the kinetics of amyloid formation and for screening potential inhibitors; however, we show that they can lead to false positives with hydroxyflavones. Several of the compounds inhibit thioflavin-T fluorescence, but not amyloid formation; a result which highlights the hazards of relying solely on thioflavin-T assays to screen potential inhibitors. Transmission electron microscopy (TEM) and right-angle light scattering show that Morin hydrate (2',3,4',5,7-Pentahydroxyflavone) inhibits amyloid formation by human IAPP and disaggregates preformed IAPP amyloid fibers. In contrast, Myricetin, Kaempferol, and Quercetin, which differ only in hydroxyl groups on the B-ring, are not effective inhibitors. Morin hydrate represents a new type of IAPP amyloid inhibitor and the results with the other compounds highlight the importance of the substitution pattern on the B-ring. 相似文献
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《朊病毒》2013,7(4):256-264
Evidence is growing at an increasing pace that amyloid fibers are not just the result of aberrant protein folding associated with neurodegenerative diseases, but are widespread in Nature for beneficial reasons. Amyloid is an attractive building material because its robust design and simple repetitive structure makes for very durable and metabolically cheap material. But this requires that the production of amyloid be put under firm control. This appears to involve the use of 4-5 chaperones which are expressed under the control of the same promoter as the amyloid proteins. Significant progress has been made in deciphering this process in E. coli’s csg operon, also found in Salmonella. Recently, we have discovered a new and unrelated operon (fap) responsible for amyloid production in Pseudomonas, which also confers biofilm forming properties to E. coli. Intriguingly, this operon shares a number of features with csg, namely two homologous proteins (one of which, FapC, has been shown to be directly involved in amyloid build-up) and a small number of auxiliary proteins. However, FapC seems to be less economically structured than its E. coli counterpart, with a smaller number of repeats and very large and variable linker regions. Furthermore, the putative chaperones are not homologous to their csg counterparts and have intriguing homologies to proteins with other functions. These findings suggest that controlled amyloid production has arisen on many independent occasions due to the usefulness of the product and offers the potential for intriguing insights into how Nature disarms and reconstructs a potentially very dangerous weapon. 相似文献
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The interplay of genetics and the environment in the etiology of Alzheimer's disease (AD) is not well understood. Now, Lazarov and coworkers show that a simple paradigm of environmental enrichment alleviates amyloid burden and alters disease-associated gene expression changes in a double transgenic mouse model of AD. 相似文献
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Of 10 variation sites between sequences of amyloid-resistant porcine islet amyloid polypeptide (pIAPP) and amyloid-prone human IAPP (hIAPP), seven locate within residues 17–29, the most amyloidogenic fragment within hIAPP. To investigate how these variations affect amyloidogenicity, 26 IAPP(17–29) or IAPP(20–29) variants were synthesized and their secondary structures, amyloidogenicity, oligomerization and cytotoxicity were studied. Our results indicated that pIAPP fragments are refractory to amyloid formation and significantly less cytotoxic compared with hIAPP fragments. A novel stable dimer was observed in pIAPP(20–29) solution, whereas hIAPP(20–29) exists mostly as monomers and trimers. Among all human to porcine substitutions, S20R caused the most prolonged lag time and significantly attenuated cytotoxicity. The different oligomerization and amyloidogenic properties of hIAPP and pIAPP fragments are discussed.
Structured summary
pIAPP and pIAPPbind: shown by molecular sieving (view interactions 1, 2)hIAPP and hIAPPbind: shown by molecular sieving (view interactions 1, 2) 相似文献9.
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Jang Soyoung Jang Woo Young Choi Minjee Lee Jinhee Kwon Wookbong Yi Junkoo Park Si Jun Yoon Duhak Lee Sanggyu Kim Myoung Ok Ryoo Zae Young 《Transgenic research》2019,28(5-6):499-508
Transgenic Research - Alzheimer's disease (AD) is a neurodegenerative disorder, characterized by cognitive impairment, progressive neurodegeneration, and amyloid-β (Aβ) lesion. In the... 相似文献
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Caspase cleavage of the amyloid precursor protein modulates amyloid beta-protein toxicity 总被引:1,自引:0,他引:1
The amyloid beta-protein precursor (APP) is proteolytically cleaved to generate the amyloid beta-protein (Abeta), the principal constituent of senile plaques found in Alzheimer's disease (AD). In addition, Abeta in its oligomeric and fibrillar forms have been hypothesized to induce neuronal toxicity. We and others have previously shown that APP can be cleaved by caspases at the C-terminus to generate a potentially cytotoxic peptide termed C31. Furthermore, this cleavage event and caspase activation were increased in the brains of AD, but not control, cases. In this study, we show that in cultured cells, Abeta induces caspase cleavage of APP in the C-terminus and that the subsequent generation of C31 contributes to the apoptotic cell death associated with Abeta. Interestingly, both Abeta toxicity and C31 pathway are dependent on the presence of APP. Both APP-dependent Abeta toxicity and C31-induced apoptotic cell death involve apical or initiator caspases-8 and -9. Our results suggest that Abeta-mediated toxicity initiates a cascade of events that includes caspase activation and APP cleavage. These findings link C31 generation and its potential cell death activity to Abeta cytotoxicity, the leading mechanism proposed for neuronal death in AD. 相似文献
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Masaki Wakabayashi 《FEBS letters》2009,583(17):2854-36097
Human islet amyloid polypeptide (hIAPP) is the primary component of the amyloid deposits found in the pancreatic islets of patients with type 2 diabetes mellitus. However, it is unknown how amyloid fibrils are formed in vivo. In this study, we demonstrate that gangliosides play an essential role in the formation of amyloid deposits by hIAPP on plasma membranes. Amyloid fibrils accumulated in ganglioside- and cholesterol-rich microscopic domains (‘lipid rafts’). The depletion of gangliosides or cholesterol significantly reduced the amount of amyloid deposited. These results clearly showed that the formation of amyloid fibrils was mediated by gangliosides in lipid rafts. 相似文献
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K Miura S Baba H Shirasawa S T Ju A S Cohen T Shirahama 《Virchows Archiv. B, Cell pathology including molecular pathology》1992,62(4):245-250
Although resident peritoneal cells from amyloidotic mice (amyloidotic peritoneal cells) are capable of processing the precursor protein of secondary amyloidosis, serum amyloid A (SAA) to amyloid fibrils, the peritoneum is a rare site for amyloid deposition. This is considered to be due to a deficiency of SAA in the peritoneum. To increase the supply of SAA to the peritoneum, ascitic fluid containing about the same protein constituents as in the serum was induced in mice. Amyloidotic peritoneal cells were packed in a microchamber which was shielded with filter membranes, and cultured in ascitic fluid supplemented with additional inflammatory factors. On the 7th day, Congo red-positive structures which showed green birefringence under polarized light were found inside and occasionally outside the chamber. By anti-AA or -SAA immunostaining, amyloid deposits and the cell surfaces of macrophages were positive. Immunologic depletion of T- and B-lymphocytes from the amyloidotic peritoneal cells did not adversely effect the amyloid formation in microchambers. These results suggest that either ascitic fluid containing sufficient amounts of SAA, or peritoneal macrophages with a high amyloid enhancing factor (AEF) activity are indispensable for AA amyloid fibrillogenesis in the peritoneum. 相似文献
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The amyloid formation of phosphoglycerate kinase (PGK) was investigated by static and dynamic light-scattering. The time-course of the scattering intensity and the hydrodynamic radius scale with initial monomer concentration in a linear fashion over a range of about 50 in concentration. This sets limits on theories for aggregation kinetics that can be used, and points towards irreversible, cascade type models. In addition, circular dichroism (CD) was used to monitor the transition between a predominantly alpha-helical spectrum to a beta-sheet enriched one. The time-course of the CD also proves to scale linearly with initial monomer concentration. Electron microscopy shows that small oligomers as well as protofibrils are present during aggregation. The found coupling between growth of intermediates and acquisition of beta-sheet structure is interpreted in terms of a generalized diffusion-collision model, where stabilization of beta-strands takes place by intermolecular interactions. 相似文献
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Söderberg L Dahlqvist C Kakuyama H Thyberg J Ito A Winblad B Näslund J Tjernberg LO 《The FEBS journal》2005,272(9):2231-2236
Recently, a novel plaque-associated protein, collagenous Alzheimer amyloid plaque component (CLAC), was identified in brains from patients with Alzheimer's disease. CLAC is derived from a type II transmembrane collagen precursor protein, termed CLAC-P (collagen XXV). The biological function and the contribution of CLAC to the pathogenesis of Alzheimer's disease and plaque formation are unknown. In vitro studies indicate that CLAC binds to fibrillar, but not to monomeric, amyloid beta-peptide (Abeta). Here, we examined the effects of CLAC on Abeta fibrils using assays based on turbidity, thioflavin T binding, sedimentation analysis, and electron microscopy. The incubation of CLAC with preformed Abeta fibrils led to increased turbidity, indicating that larger aggregates were formed. In support of this contention, more Abeta was sedimented in the presence of CLAC, as determined by gel electrophoresis. Moreover, electron microscopy revealed an increased amount of Abeta fibril bundles in samples incubated with CLAC. Importantly, the frequently used thioflavin T-binding assay failed to reveal these effects of CLAC. Digestion with proteinase K or trypsin showed that Abeta fibrils, incubated together with CLAC, were more resistant to proteolytic degradation. Therefore, CLAC assembles Abeta fibrils into fibril bundles that have an increased resistance to proteases. We suggest that CLAC may act in a similar way in vivo. 相似文献